Many drugs of abuse target dopaminergic neurotransmission in the striatum. It is important to biochemically characterize intracellular signal transduction both in post-synaptic dopaminoceptive neurons of striatum and in pre-synaptic dopaminergic neurons of the midbrain in order to provide clearer information about how numerous, interacting signaling cascades are altered by drug addiction. Previously, we have shown that the neuronal protein kinase, Cdk5 (cyclin-dependent kinase-5), is an important regulator of dopaminergic neurotransmission. Furthermore, we have shown that Cdk5 and its neuron-specific activating cofactor, p35, are targets of chronic cocaine exposure. More recently, we have found that chronic cocaine-induced effects on neuronal synaptic morphology in the nucleus accumbens, the ventral portion of the striatum, which is particularly important for cocaine's behavioral effects, are under the control of Cdk5. We now propose to further characterize the role of Cdk5 in striatal brain function and determine its role in the processes that contribute to the addictive state. Toward this goal, we will investigate the ability of Cdk5 to regulate the activity of a striatal post-synaptic target (protein phosphatase inhibitor-1), and a pre-synaptic target tyrosine hydroxylase). In addition, we will search, using a proteomic approach, for additional proteins that mediate Cdk5-dependent processes in the striatum that contribute to cocaine action. The goal of this work is to identify new targets and therefore new biomolecular mechanisms underlying drug addiction. This information may also serve as the basis for the development of novel treatments for this disorder.